PMID- 16221210
OWN - NLM
STAT- MEDLINE
DCOM- 20060120
LR  - 20091119
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 68
IP  - 5
DP  - 2005 Nov
TI  - Soluble fibronectin induces chemokine gene expression in renal tubular epithelial 
      cells.
PG  - 2111-20
AB  - BACKGROUND: Increasing proteinuria in kidney disease is associated with an 
      increased risk of renal failure. Urinary proteins such as albumin induce 
      inflammatory signaling and gene expression in tubular epithelial cells (TECs). 
      Fibronectin is an extracellular matrix protein that can exist in soluble form and 
      is excreted in the urine of patients with glomerular disease. METHODS: To explore 
      the impact of soluble fibronectin on tubular epithelium, murine TECs were 
      stimulated with soluble fibronectin and chemokine mRNA was determined by RNase 
      protection assay. RESULTS: Fibronectin induced the expression of inflammatory 
      chemokine genes, including monocyte chemoattractant protein-1 (MCP-1) (CCL2) and 
      macrophage inflammatory protein-2 (MIP-2) within 2 hours in a dose-dependent 
      manner. Phosphorylation of Src family tyrosine kinases was also increased in TECs 
      following exposure to fibronectin. Src tyrosine kinases were involved in the 
      fibronectin activation of MCP-1 since the Src inhibitors SU6656 and PP2 
      effectively reduced the induction of this chemokine. Fibronectin also induced the 
      phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) within 
      minutes in TECs. The ERK kinase (MEK1/2) inhibitor U0126 inhibited the 
      fibronectin induction of MCP-1 mRNA suggesting that ERK1/2 was also involved in 
      this inflammatory pathway. Furthermore, fibronectin also induced phosphorylation 
      of IkappaBalpha within 20 minutes in TECs. The nuclear factor-kappaB (NF-kappaB) 
      inhibitors N-acetyl-L-cysteine (NAC) and pyrrolidinecarbodithioic acid (PDTC) 
      effectively blocked fibronectin induction of MCP-1 mRNA. CONCLUSION: Soluble 
      fibronectin activates MCP-1 gene expression in TECs via Src tyrosine kinases, 
      ERK1/2 and NF-kappaB. These data provide further support to the concept that 
      proteinuria per se contributes to the tubulointerstitial injury observed in 
      glomerular disease.
FAU - Ren, Li
AU  - Ren L
AD  - Division of Nephrology, Department of Medicine, University of Calgary, Alberta, 
      Canada.
FAU - Blanchette, Jason B
AU  - Blanchette JB
FAU - White, Lindsay R
AU  - White LR
FAU - Clark, Sharon A
AU  - Clark SA
FAU - Heffner, Daniel J
AU  - Heffner DJ
FAU - Tibbles, Lee Anne
AU  - Tibbles LA
FAU - Muruve, Daniel A
AU  - Muruve DA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CXCL2)
RN  - 0 (Chemokines)
RN  - 0 (Cxcl2 protein, mouse)
RN  - 0 (Fibronectins)
RN  - 0 (NF-kappa B)
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics
MH  - Chemokine CXCL2
MH  - Chemokines/*genetics
MH  - Epithelial Cells/cytology/*drug effects/immunology
MH  - Fibronectins/*pharmacology
MH  - Gene Expression/drug effects/immunology
MH  - Kidney Tubules/*cytology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - NF-kappa B/metabolism
MH  - Solubility
MH  - src-Family Kinases/metabolism
EDAT- 2005/10/14 09:00
MHDA- 2006/01/21 09:00
CRDT- 2005/10/14 09:00
PHST- 2005/10/14 09:00 [pubmed]
PHST- 2006/01/21 09:00 [medline]
PHST- 2005/10/14 09:00 [entrez]
AID - S0085-2538(15)51107-1 [pii]
AID - 10.1111/j.1523-1755.2005.00667.x [doi]
PST - ppublish
SO  - Kidney Int. 2005 Nov;68(5):2111-20. doi: 10.1111/j.1523-1755.2005.00667.x.